PROJECT SUMMARY Alzheimer?s disease (AD) is a progressive neurodegenerative disorder of the elderly that afflicts about 30 million patients globally and over 5 million Americans in the US. Despite the considerable research effort to prevent, treat, or cure the disease, effective strategies remain lacking. The accumulation of amyloid-? (A?) in the brain blood vessels can result in the development of cerebral amyloid angiopathy (CAA). CAA is a pathological feature present concomitantly with AD at a high frequency, highlighting a potentially important role for vascular A? in dementias such as AD. Currently no treatment is available to slow or stop the progression of CAA and AD. The purpose of this application is to evaluate oleocanthal (OC), a natural phenolic compound isolated from extra-virgin olive oil, as a novel molecule with neuroprotective effects against AD in a mouse model. The overall goal of this project is to generate data to inform the commercialization pathways Oleolive will follow for OC and guide the company development strategy to be proposed in a Phase II SBIR. The central hypothesis is that low dose nano-emulsions of OC in water fed to mice will be effective as a preventive and therapeutic in mouse models of AD. This hypothesis will be tested by pursuing the following specific aims: Aim 1) Perform dose-dependent studies to determine the optimum protective dose of orally administered OC. This Aim will be examined via the Sub-Aims: a) evaluate OC effect on BBB integrity, vascular and cerebral A? load, and synaptic integrity, and b) evaluate OC effect on efficacy and toxicity biomarkers. Aim 2) Evaluate the effect of orally administered OC on metabolic and behavior phenotypes. Methods and techniques to be used to accomplish the above aims include in vivo studies in AD mouse model, biochemical analysis, microvessels isolation from mice brains, toxicity and histopathology studies, and metabolic and behavior phenotype studies. Findings from this work are expected to confirm OC as a novel molecule to prevent and/or treat AD and related dementias and would support and advance OC therapeutic development toward clinical trials.